Professional Documents
Culture Documents
This is our recommended approach to COVID-19 based on the best (and most recent) literature. This is a
highly dynamic topic; therefore, we will be updating the guideline as new information emerges.
EVMS COVID website: https://www.evms.edu/covid-19/medical_information_resources/
Short url: evms.edu/covidcare
Prophylaxis
While there is no “Level 1 evidence” that this “cocktail” will prevent/mitigate against COVID-19 we
believe there is significant evidence supporting the efficacy of the individual agents included in the
prophylactic protocol. This protocol MUST be part of an overall strategy which includes common sense
public health measures, i.e. masks, social distancing, and avoidance of large groups of people.
Furthermore, it should be noted that there is emerging evidence suggesting that IVERMECTIN may be
highly effective in the prevention and treatment of COVID-19. It is important to emphasize that ALL of
the medications included in our prophylactic regimen are inexpensive, safe, and widely available.
• Vitamin D3 1000–3000 IU/day. Note RDA (Recommended Daily Allowance) is 800–1000 IU/day.
The safe upper-dose daily limit is likely < 4000 IU/day. [1-22] Vitamin D insufficiency has been
associated with an increased risk of acquiring COVID-19 and from dying from the disease.
Vitamin D supplementation may therefore prove to be an effective and cheap intervention to
lessen the impact of this disease, particularly in vulnerable populations, i.e. the elderly, those of
color, obese and those living > 45o latitude. [7-22]
• Vitamin C 500 mg BID (twice daily) and Quercetin 250 mg daily. [23-34] It is likely that vitamin C
and quercetin have synergistic prophylactic benefit. [35] It should be noted that in vitro studies
have demonstrated that quercetin and other flavonoids interfere with thyroid hormone
synthesis at multiple steps in the synthetic pathway. [36-39] The use of quercetin has rarely
been associated with hypothyroidism. The clinical impact of this association may be limited to
those individuals with pre-existent thyroid disease or those with sub-clinical thyroidism.[40] In
women high consumption of soya was associated with elevated TSH concentrations.[41] The
effect on thyroid function may be dose dependent, hence for chronic prophylactic use we
suggest that the lowest dose be taken. Quercetin should be used with caution in patients with
hypothyroidism and TSH levels should be monitored. It should also be noted quercetin may have
important drug-drug interactions; the most important drug-drug interaction is with cyclosporin
and tacrolimus. [42] In patients taking these drugs it is best to avoid quercetin; if quercetin is
taken cyclosporin and tacrolimus levels must be closely monitored.
• Melatonin (slow release): Begin with 0.3 mg and increase as tolerated to 2 mg at night. [43-50]
• Zinc 30–50 mg/day (elemental zinc). [23,30,32,33,51-55]
• B complex vitamins [56-60]
• Ivermectin for postexposure prophylaxis (see ClinTrials.gov NCT04422561). 0.2 mg/kg (12 mg)
immediately then repeat day 3.
• Ivermectin for pre-exposure prophylaxis (in HCW) and for prophylaxis in high-risk individuals
(> 60 years with co-morbidities, morbid obesity, long term care facilities, etc). 0.15–0.2 mg/kg
Day 1, Day 3 and then weekly for 10 weeks, followed by biweekly dosing. [5,61-64] (also see
ClinTrials.gov NCT04425850). See dosing Table below. NB. Ivermectin has a number of
potentially serious drug-drug interactions. Please check for potential drug interaction at
Ivermectin Drug Interactions - Drugs.com. The most important drug interactions occur with
cyclosporin, tacrolimus, anti-retroviral drugs, and certain anti-fungal drugs.
Note: A falling SaO2 and the requirement for supplemental oxygen should be a trigger to start anti-
inflammatory treatment (see Figure 2).
Note: Early termination of ascorbic acid and corticosteroids will likely result in a rebound effect with
clinical deterioration (see Figure 6).
4. Highly recommended: Ivermectin 0.15–0.2 mg/kg orally and repeat on day 2 (see doing above).
[1-3,67,70-78,134-136,187-193] Note that ivermectin has potent antiviral and ant-inflammatory
effects. See Table 1 and Figure 5.
5. Melatonin 10 mg at night (the optimal dose is unknown).
6. Calcifediol 0.2–0.5 mg. [66] This should be followed by 0.2 mg calcifediol weekly until discharged
from hospital. Vitamin D3 takes many days to be converted to 25OH vitamin D; [194] this may
explain the lack of benefit of D3 in patients hospitalized with severe COVID-19. [195]
7. Thiamine 200 mg IV q 12 hourly [196-201] Thiamine may play a role in dampening the cytokine
storm. [197]
8. ASA 325 mg. COVID infection results in profound platelet activation contributing to the severe
pro-thrombotic state and increasing the inflammatory response.[151-153] As the risk of
significant bleeding is increased in patients receiving both ASA and heparin, ASA should therefore
not be used in patients at high risk of bleeding. In addition (as noted below) patients should
receive famotidine concurrently.
9. B complex vitamins
10. Magnesium: 2 g stat IV. Keep Mg between 2.0 and 2.4 mmol/l. [59] Prevent hypomagnesemia
(which increases the cytokine storm and prolongs Qtc). [202-204]
A sub-group of patients with COVID-19 deteriorates very rapidly. Intubation and mechanical
ventilation may be required in these patients.
26. Monitoring
• On admission: Procalcitonin (PCT), CRP, BNP, Troponins, Ferritin, Neutrophil-Lymphocyte
ratio, D-dimer and Mg. CRP and D-dimer are important prognostic markers. A PCT is
essential to rule out coexisting bacterial pneumonia.
• Daily: CRP, Ferritin, D-Dimer and PCT. CRP and Ferritin track disease severity closely (although
ferritin tends to lag behind CRP). Early high CRP levels are closely associated with the degree
of pulmonary involvement and the CT score. [262]
• In patients receiving IV vitamin C, the Accu-Chek™ POC glucose monitor will result in
spuriously high blood glucose values. Therefore, a laboratory glucose is recommended to
confirm the blood glucose levels. [263,264]
• No routine CT scans, follow CXR and chest ultrasound.
• ECHO as clinically indicated; Pts may develop a severe “septic” cardiomyopathy.
‘Misinformation on the Coronavirus might be the most contagious thing about it”
Dr. Tedros, WHO Director General
• The Panic and misinformation spread by Social Media travels faster than the pandemic
itself. What you can do?
o Avoid social media as much as possible; excess social media exposure increases
the likelihood of anxiety and depression[279]
o Read the news/information from reliable sources (if you can find one)
o Have a designated time for checking information
o People share false claims about COVID-19 partly because they simply fail to
think sufficiently about whether or not the content is accurate when deciding
what to share. [280]
o Stay connected to positive people! Remotely!
o Have a plan for staying in touch with family and friends
o Identify positive influencers…limit contact with other “worriers”
o Isolation can cause rumination/anxious thinking to escalate
o Maintain a sense of hope, humanity and kindness toward others
o Seek professional help if anxiety is overwhelming
• Recognize the things you can control
o WEAR A MASK when in contact with others
o Establish social distancing; stand/sit about 6 feet away from others
o Limit attendance at large gatherings
o Eliminate your contact with those who are ill
o DON’T go to work or school if you are sick
o Practice self-care
Good sleep, balanced diet, exercise
Mindfulness/Meditation/Relaxation activities
1. Patients transition through a number of different phases (clinical stages). The treatment of each
phase is distinct ... this is critically important (see Figures 1 & 2).
2. Antiviral therapy is likely to be effective only during the viral replicative phase whereas anti-
inflammatory therapy is expected to be effective during the pulmonary phase and possibly the
post-COVID-19 phase. While Remdesivir is a non-specific antiviral agent that targets RNA
viruses, it is likely that agents specifically designed to target SARS-CoV-2 will be developed.
3. The SARS-CoV-2 PCR remains positive for at least 2 weeks following detection of whole virus (by
culture, See figure 3). Patients who progress to the pulmonary phase are usually PCR positive
despite cessation of viral replication (and are therefore less likely to be infectious).
4. Due to the imperfect sensitivity of the PCR test as many as 20% of patients who progress to the
pulmonary phase will be PCR negative (even on repeat testing). At symptom onset PCR will be
positive in approximately 60% of patients; maximal positivity rate is on day 8 (post infection)
when 80% of patients will be positive (see Figure3). [281]
5. Symptomatic patients are likely to be infectious during a narrow window starting 2–3 days
before the onset of symptoms and to up to 6 days after the onset of symptoms (see Figure
3).[282]
6. It is important to recognize that COVID-19 patients present with a variety of phenotypes, likely
dependent on inoculum size and viral load, genetic heterogeneity mutations and
polymorphisms, biotypes, blood type, sex and androgen status, age, race, BMI (obesity),
immunological and nutritional status, and co-morbidities.[157,283-293] The phenotype at
presentation determines the prognosis and impacts the optimal approach to treatment.
7. The pulmonary phase is characterized by immune dysregulation, [246,248,256,259,260,286,294-
303] a pulmonary microvascular injury (vasculopathy),[256,303-306] with activation of clotting
and a pro-coagulant state together with the characteristics of an organizing pneumonia.
[307,308]
8. Endothelial damage and an imbalance of both innate and adaptive immune responses, with
aberrant macrophage activation, plays a central role in the pathogenesis of the severe COVID-19
Disease. [256]
9. As patients, progress down the pulmonary cascade the disease becomes more difficult to
reverse. The implications of this are twofold.
a. Early treatment (of the pulmonary phase) is ESSENTIAL to a good outcome.
b. Treatment in the late pulmonary phase may require escalation of the dose of
corticosteroids as well as the use of salvage methods (i.e. plasma exchange). However,
patients who present in the late pulmonary phase may have progressed to the
irreversible pulmonary fibroproliferative phase (see Figure 9).
10. The pulmonary phase of COVID-19 is a treatable disease; it is inappropriate to limit therapy to
“supportive care” alone. Furthermore, it is unlikely that there will be a single “silver bullet” to
treat severe COVID-19 disease. Rather, patients will require treatment with multiple
drugs/interventions that have synergistic and overlapping biological effects. Repurposed FDA
approved drugs that are safe, inexpensive, and “readily” available are likely to have a major
therapeutic effect on this disease. The impact of COVID-19 on middle- and low-income countries
is enormous; these countries are not able to afford expensive propriety “designer” molecules.
11. The radiographic and pathological finding of COVID-19 lung disease are characteristic of a
secondary organizing pneumonia (and not ARDS). [307,309,310]
The above pathologies are not novel, although the combined severity in COVID-19 disease is
considerable. Our long-standing and more recent experiences show consistently successful treatment if
traditional therapeutic principles of early and aggressive intervention is achieved, before the onset of
advanced organ failure. It is our collective opinion that the historically high levels of morbidity and
mortality from COVID-19 is due to a single factor: the widespread and inappropriate reluctance amongst
hospitalists and intensivists to employ anti-inflammatory and anticoagulant treatments, including
corticosteroid therapy early in the course of a patient’s hospitalization. It is essential to recognize that
it is not the virus that is killing the patient, rather it is the patient’s overactive immune system.
[245,248,256,321] Autopsy studies have demonstrated minimal viral cytopathic effects.[256,321] The
flames of the “cytokine fire” are out of control and need to be extinguished. Providing supportive care
(with ventilators that themselves stoke the fire) and waiting for the cytokine fire to burn itself out simply
does not work… this approach has FAILED and has led to the death of tens of thousands of patients.
“If what you are doing ain’t working, change what you are doing” – PEM
The systematic failure of critical care systems to adopt corticosteroid therapy (early in this pandemic)
resulted from the published recommendations against corticosteroids use by the World Health
Organization (as recent as May 27th 2020) [349,350]. This recommendation was then perpetuated by the
Centers for Disease Control and Prevention (CDC), the American Thoracic Society (ATS), Infectious
Diseases Association of America (IDSA) amongst others. A publication authored one of the members of
the Front Line COVID-19 Critical Care (FLCCC) Alliance (UM), identified the errors made by these
organizations in their analyses of corticosteroid studies based on the findings of the SARS and H1N1
pandemics.[154,351] Their erroneous recommendation to avoid corticosteroids in the treatment of
COVID-19 has led to the development of myriad organ failures which have overwhelmed critical care
systems across the world and led to excess deaths. The recently published results of the RECOVERY-
DEXAMETHASONE study provide definitive and unambiguous evidence of the lifesaving benefits of
corticosteroids and strong validation of the MATH + protocol. It should be recognized that
corticosteroids are the only therapy proven to reduce the mortality in patients with COVID-19.[352] The
Our treatment protocol targeting the key pathologic processes has been highly successful,
if begun within 6 hours of a COVID19 patient presenting with shortness of breath and/or arterial
desaturation and requiring supplemental oxygen. If such early initiation of treatment could be
systematically achieved, the need for mechanical ventilators and ICU beds will decrease dramatically.
Further resources:
The reader is referred to the large autopsy series by Bruce and colleagues which clearly outlines the
pathophysiology of severe COVID-19 disease.[256]
The scientific rationale for the MATH + protocol is reviewed in this paper.[171]
In this U-tube video, Professor Britt Glaunsinger, PhD provides an outstanding review on the molecular
virology of SARS-CoV-2: https://www.youtube.com/watch?v=DQVpHyvz4no
1. Gorial FI, Mashhadani S, Sayaly HM, Dakhil BD, AlMashhadani MM. Effectiveness of Ivermectin as add-on
therapy in COVID-19 management (Pilot Trial). medRxiv 2020.
2. Khan MS, Khan MS, Debnath Cr, Nath PN, Mahtab MA. Ivermectin treatment may improve the prognosis
of patients with COVID-19. Archivos de Bronconeumologia 2020.
3. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. ICON (Ivermectin in COvid Ninteen) study: Use
of ivermectin is associated with lower mortality in hospitalized patients with COVID-19. Chest 2020.
4. Niaee MS, Gheibl N, Namdar P, Allami A, Javadi A. Ivermectin as an adjunct treatment for hospitalized
adult COVID-19 patients: A randomized multi-center clinical trial. Research Square 2020.
5. Elgazzar A, Hany B, Youssef SA, Hany B, Hafez M. Efficacy and safety of ivermectin for treatment and
prophylaxis of COVID-19 pandemic. Research Square 2020.
6. Hashim HA, Maulood MF, rasheed AM, Fatak DF, Kabah KK. Controlled randomized clinical trial on using
Ivermectin with Doxycycline for treating COVID-19 patients in Bagdad, Iraq. medRxiv 2020.
7. Maghbooli Z, Sahraian MA, Ebrahimi M, Pazoki M, Kafan S. Vitamin D sufficiency, a serum 25-
hydroxyvitamin D at least 30 ng/ml reduced risk for adverse clinical outcomes in patients with COVID-19
infection. PloS ONE 2020; 15:e0239799.
8. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French Cb, Aliaono JL. Evidence that Vitamin D
supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020;
12:988.
9. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2 positivity rates associated with circulating
25-hydroxyvitamin D level. PloS ONE 2020; 15:e0239252.
10. Lau FH, Majumder R, Torabi R, Saeg F, Hoffman R, Cirillo JD. Vitamin D insufficiency is prevalent in severe
COVID-19. medRxiv 2020.
11. Marik PE, Kory P, Varon J. Does vitamin D status impact mortlality from SARS-CoV-2 infection? Medicine in
Drug Discovery 2020.
12. Rhodes JM, Subramanian S, Laird E, Kenny RA. Editorial: Low population mortality from COVID-19 in
countries south of 35 degrees North - supports vitamin D as a factor determining severity. Alimentary
Pharmacology & Therapeutics 2020; (in press).
13. Dancer RC, Parekh D, Lax S et al. Vitamin D deficiency contributes directly to the acute respiratory distress
syndrome (ARDS). Thorax 2015; 70:617-24.
14. LLie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019
infection and mortality. Aging Clin Exp Res 2020.
15. Daneshkhah A, Eshein A, Subramanian H. The role of vitamin D in suppressing cytokine storm of COVID-19
patients and associated mortality. medRxiv 2020.
16. Bergman P, Lindh AU, Bjorkhem-Bergman L, Lindhagen L. Vitamin D and respiartory tract infections: A
systematic review and meta-analysis of randomized controlled trials. PloS ONE 2013; 8:e65835.
17. Carpagnano GE, Lecce V, Quaranta VN, Zito A, Buonamico E. Vitamin D deficiency as a predictor of poor
prognosis in patients with acute respiratory fialure due to COVID-19. J Endocrinol Invest 2020.
18. Israel A, Cicurel A, Feldhamer I et al. The link between vitamin D deficiency and Covid-19 in a large
population. medRxiv 2020.
19. Radujkovic A, Hippchen T, Tiwari-Heckler S, Dreher S, Merle U. Vitamin D deficiency and outcome of
COVID-19 patients. Nutrients 2020; 12:2757.
20. Rizzoli R. Vitamin D supplementation: upper limit for safety revisited. Aging Clin Exp Res 2020.
21. Annweiler C, Hanotte B, de L'Eprevier CG, Sabatier JM, Lafaie L. Vitamin D and survival in COVID-19
patients: A quasi-experimental study. Journal of Steroid Biochemistry & Molecular Biology 2020.
22. Moozhipurath RK, Kraft L, Skiera B. Evidence of protective role of Ultraviolet-B (UVB) radiation in reducing
COVID-19 deaths. Nature Research 2020; 10:17705.
23. Maggini S, Beveridge S, suter M. A combination of high-dose vitamin C plus zinc for the common cold.
Journal of International Medical Research 2012; 40:28-42.
24. Colunga Biancatelli RM, Berrill M, Catravas JD, Marik PE. Quercetin and Vitamin C: experimental therapy
for the prevention and treatment of SARS-CoV-2 via synergistic action. Front Immunol 2020.
25. Kyung Kim T, Lim HR, Byun JS. Vitamin C supplementaion reduces the odds of developing a common cold
in Republic of Korea Army recruits: a randomised controlled trial. BMJ Mil Health 2020.